Several advances have been made during the past year in both basic research and in translational research. One major advance in basic research has been the demonstration of the involvement of DNA double strand breaks (DSBs) in the """"""""bystander effect"""""""" (1). The bystander effect is the appearance of genome instability in cells that have themselves not been subjected to any DNA damage-inducing agent but which have been in contact with either cells or media from cells that have been subjected to a DNA damaging agent. The importance of understanding the bystander effect stems from the finding that it is greatest at low levels of damage and therefore can substantially magnify the apparent effect of clastogenic agents, resulting in chromosome rearrangements, micronuclei, and other signs of genomic instability in greater numbers of cells than predicted from the experimental parameters. Thus understanding the bystander effect is an essential part of understanding genome stability in eucaryotic organisms. In addition to discovering DNA DSB involvement in various cellular processes, we have also found mechanistic interactions between gamma-H2AX and other cellular processes (2). He has shown that efficient repair also requires proteins involved in chromatid cohesion: Csm3; Tof1; Mrc1, and Dcc1. These studies suggest a role for H2A serine 129 in the establishment of specialized cohesion structure necessary for the normal repair of topoisomerase I-induced DNA damage. Collaborations are being arranged with NCI Clinical Research Branches As an initial examination of its potential, we are collaborating with other NCI investigators in measuring gamma-H2AX formation after cellular drug exposure in a clinical study (ABT-888, aminoflavone, SJG-136). 1. Sokolov MV, Smilenov LB, Hall EJ, Panyutin IG, Bonner WM, Sedelnikova OA. Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts. Oncogene. 2005 Nov 10;24(49):7257-65. 2. Redon C, Pilch DR, Bonner WM. Genetic analysis of Saccharomyces cerevisiae H2A serine 129 mutant suggests a functional relationship between H2A and the sister-chromatid cohesion partnersCsm3-Tof1 for the repair of topoisomerase I-induced DNA damage. Genetics. 2006 Jan;172(1):67-76.
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